The translational goal of this project is to develop simple blood tests to predict colon cancer risk and to tailor therapy for colorectal intraepithelial neoplasia (IEN). Diagnosis of colon cancer at an early stage continues to be problematic, and response to treatment is limited in late stage colon cancer. Better measures of risk will contribute to colon IEN prevention or earlier detection. Earlier detection combined with methodologies to predict response to therapy will decrease colon cancer incidence and mortality. The hypothesis to be tested in this proposal is that the risk of colorectal cancer is influenced by genetic variability affecting the expression/function of the adenomatous polyposis coli (APC) tumor suppressor gene and/or APC modifier genes, such as ornithine decarboxylase (ODC). Measures of this genetic variability may be prognostic and/or predictive factors for colorectal IEN. To test this hypothesis, four specific aims are proposed. First, we will measure specific mutations in the APC tumor suppressor gene in colorectal adenomas from participants in colon cancer prevention trials. Second, we will measure germline polymorphism frequencies in codon 1822 of APC. We will determine associations between genetic variability in APC with dietary factors and adenoma recurrence in this patient group. Third, we will measure the genetic variability in the c-myc-dependent region of the ODC promoter in groups at risk for colorectal IEN, and determine whether polymorphisms are associated with adenoma recurrence. Finally, we will ascertain the functional significance of these polymorphisms in intestinal carcinogenesis. Future studies will measure variability in other downstream mediators of APC. These other mediators include networks regulating polyamine and arachidonic acid metabolism. Since these pathways are targets for IEN therapy (e.g., DFMO, NSAIDs), genetic variability in these pathways may be predictive factors for therapeutic response to treatment.